Developmental Consequences of Birth Interventions

说明(申请人提供)：已知催产素可调节社会行为、应激反应、心理健康、心血管和免疫系统，部分是通过中枢和自主神经系统的作用。初步研究表明，在生命早期接触外源性合成催产素可以对依赖内源性催产素的行为、神经系统和基因产生持久的表观遗传影响。这项拟议的转译研究将提供第一个专门针对测试与分娩过程相关的催产素暴露的行为、内分泌、自主神经和表观遗传学后果的动物模型。虽然可能全身许多系统都受到催产素的影响，但我们首先将重点放在已知对内源性催产素敏感的神经过程和遗传途径上，包括催产素及其相关多肽、精氨酸加压素(AVP)的基因表达，以及每种催产素的特定受体。通过一系列相关的项目，我们将研究(A)在出生期间暴露于合成催产素(Pitocin)的后果，这种合成催产素通常用于以后的诱导或增强，以及(B)通过暴露于用于减缓分娩过程的催产素拮抗剂(OTA)来阻断催产素受体。这一建议的具体目标是：(1)开发一种翻译动物范式，旨在模拟和研究人类出生干预的选定特征；(2)检验与出生相关的神经肽、催产素的功能存在或缺失将影响后代的行为和大脑的假设，从而影响催产素/AVP 为了更深入地了解可能受出生相关干预措施影响的神经机制，以及(4)确定催产素和其他出生相关干预措施的具体表观遗传后果，本研究的主要目的是：(1)通过基因途径(包括多肽及其受体的基因)，(3)更深入地了解可能受出生相关干预措施影响的神经机制；(4)确定催产素和其他出生相关干预措施的具体表观遗传学后果。男性和女性都将接受测试，这让我们能够检验与出生相关的干预措施的影响可能是两面性的假设。这些研究还将检验这样一种假设，即表观遗传机制最初基于催产素受体(OXTR)DNA的甲基化，允许表观基因组通过出生经历进行转化。这里描述的新开发的范例可以用来发现生育干预的表观遗传后果，并改进优化生育结果的方法。这项研究的数据还将有助于目前对社会和情绪行为的正常发育生物学的理解，并将有助于评估通常用于操纵人类分娩过程的治疗方法对婴儿的影响。这些研究还将增加我们对神经、自主神经、内分泌和表观遗传机制的基本理解，这些机制是哺乳动物基本行为的基础，包括社会行为、情绪调节以及焦虑和抑郁的行为。这里使用的动物模型是草原田鼠，它有一个类似人类的自主神经系统，一个以高度社会性和所有父母行为为特征的社会系统，长期的配对纽带和高水平的催产素在晚年采取的措施包括以下指标：(A)社会和情感行为，(B)内分泌变化，包括使用PCR测量内源性催产素和AVP及其受体的基因表达(MRNA)，(C)通过无线电遥测测量并以心率为指标的自主神经系统功能，以及迷走神经传出通路介导的心率的节律性变化，(D)通过功能磁共振成像(FMRI)测量神经激活和回路的变化，以响应社会线索；以及(E)通过详细分析催产素途径中基因的CpG DNA甲基化，测量后代基因组的表观遗传修饰，如OXTR。

DESCRIPTION (provided by applicant): Oxytocin is known to regulate social behaviors, stress reactivity, mental health, cardiovascular and immune systems, in part through actions in the central and autonomic nervous systems. Preliminary studies have shown that exposure to exogenous synthetic oxytocin in early life can have long-lasting, epigenetic effects on behavior, neural systems and genes that are dependent on endogenous oxytocin. The proposed translational research will provide the first animal model specifically aimed at testing the behavioral, endocrine, autonomic and epigenetic consequences of exposure to oxytocin associated with the birth process. Although it is likely that many systems throughout the body are affected by oxytocin, we will focus initially on neural processes and genetic pathways known to be sensitive to endogenous oxytocin, including the expression of genes for oxytocin and the related peptide, arginine vasopressin (AVP), and selected receptors for each of these. Using a series of interrelated projects we will examine the consequences of (a) exposure during birth to synthetic oxytocin (Pitocin), commonly used to induce or augment later, and (b) blocking the oxytocin receptor by exposure to oxytocin antagonists (OTA), used to slow the birth process. The specific objectives of this proposal are: (1) to develop a translational animal paradigm designed to model and study selected features of human birth-interventions, (2) to test the hypothesis that the functional presence or absence of the neuropeptide, oxytocin associated with birth will influence the behavior and brain of the offspring, with effects on the oxytocin/AVP pathway (including genes for the peptides and their receptors), (3) to gain a deeper knowledge of neural mechanisms which may be affected by birth-related interventions, and (4) to identify specific epigenetic consequences of oxytocin and other birth-related interventions. Both males and females will be tested, allowing us to examine the hypothesis that the effects of birth-related interventions may be sexually dimorphic. These studies also will test the hypothesis that epigenetic mechanisms, based initially on methylation of DNA for the oxytocin receptor {OXTR), allow the epigenome to be transformed by the birth experience. The newly developed paradigms described here can be used to discover the epigenetic consequences of birth interventions and improve methods for optimizing birth outcomes. Data from this study also will inform the present understanding of the normal developmental biology of social and emotional behaviors and will aid in the evaluation of the consequences for infants of treatments commonly used to manipulate the human birth process. These studies also will increase our basic understanding of neural, autonomic, endocrine and epigenetic mechanisms that underlie fundamental mammalian behaviors, including social behaviors, emotion regulation, and behaviors indicative of anxiety and depression. The animal model used here will be the prairie vole, which has a human-like autonomic nervous system, a social system characterized by high levels of sociality and all parental behavior, long- lasting pair bonds and high levels of oxytocin Measures to be taken in later life include indices of (a) social and emotional behaviors, (b) endocrine changes including measures of endogenous oxytocin and AVP and gene expression (mRNA) for their receptors using PCR, (c) autonomic nervous system function measured by radio telemetry and indexed by heart rate and rhythmic changes in heart rate mediated by vagal efferent pathways, (d) changes in neural activation and circuitry as measured by functional magnetic imaging (fMRI) in response to social cues, and (e) measures of epigenetic modifications of the offspring's genome, using a detailed analysis of CpG DNA methylation of genes in the oxytocin pathway, such as OXTR.